RBMX2 links infection to epithelial-mesenchymal transition and lung cancer progression.

Tuberculosis (TB) is a complex disease caused by the interaction of pathogen, host, and environmental factors. In 2022, TB affected 10.6 million people and caused 1.3 million deaths globally. In high-burden zoonotic TB regions, accounts for ~10% of human TB cases. The immune evasion and latency of hinder understanding of host responses. Here, we identify RNA-binding motif protein X-linked 2 (RBMX2) as a novel host factor facilitating infection. RBMX2 expression is significantly upregulated in multiple cell types, including EBL, BoMac, bovine alveolar primary cells, and human A549 cells. Multi-omics analyses, cell adhesion assays, and ChIP-PCR demonstrate that RBMX2 suppresses cell adhesion and tight junctions while enhancing adhesion and invasion via p65 signaling. Integrated transcriptomic, proteomic, and metabolomic data reveal that RBMX2 regulates epithelial-mesenchymal transition (EMT), a process linked to cancer progression. TIMER2.0 analysis shows elevated RBMX2 expression in lung adenocarcinoma and lung squamous cell carcinoma tissues, validated by immunofluorescence. Using an -induced BoMac-EBL EMT model and H1299 cells, we show that RBMX2 promotes EMT through p65/MMP-9 pathway activation. Collectively, RBMX2 is a novel host factor that enhances infection and drives infection-induced EMT. These findings provide new insight into TB pathogenesis and highlight RBMX2 as a potential target for TB vaccine and therapeutic development.